Medicinal composition inhibiting neovascularization proliferation factor

Abstract

A pharmaceutical composition for neovascular diseases, a pharmaceutical composition for inhibiting an angiogenic growth factor, and use of these pharmaceutical compositions are provided. In one or more embodiments, a pharmaceutical composition contains as an active ingredient a low molecular weight compound that is able to suppress the expression of VEGF gene in cells or to reduce the production of VEGF protein from cells. In one or more embodiments, a pharmaceutical composition contains as an active ingredient a compound expressed by the following formula (I) or a prodrug thereof or pharmaceutically acceptable salts thereof.

1 .- 10 . (canceled) 
     
     
         11 . A pharmaceutical composition for neovascular diseases, containing as an active ingredient a low molecular weight compound that is able to suppress expression of VEGF gene in cells or to reduce production of VEGF protein from cells. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the neovascular diseases include retinal and choroidal neovascular diseases and cancer. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein the retinal and choroidal neovascular diseases include age-related macular degeneration, glaucoma, occlusion of the retinal vein, and diabetic retinopathy. 
     
     
         14 . The pharmaceutical composition according to  claim 11 , wherein the low molecular weight compound has an ability to inhibit phosphorylation activity of a plurality of kinases. 
     
     
         15 . A pharmaceutical composition for neovascular diseases, containing as an active ingredient a compound expressed by the following formula (I) or a prodrug thereof or pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         where, in the formula (I), R 1  represents a hydrogen atom, a halogen atom, a hydroxyl group, or a substituted or unsubstituted C 1-6  alkyl group, 
         R 2  represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group (—NO 2 ), a substituted or unsubstituted C 1-6  alkyloxy group, or a substituted or unsubstituted C 1-6  alkyl group, 
         X represents NH or O, 
         Z represents a 6- or 5-membered monocyclic nitrogen-containing heterocyclic ring, or a bicyclic nitrogen-containing heterocyclic ring formed by condensation of a 6- or 5-membered nitrogen-containing heterocyclic ring and a 6- or 5-membered aliphatic ring, aromatic ring, or heterocyclic ring, 
         R 3  represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted C 1-4  alkyl group, a substituted or unsubstituted benzyl or heteroarylmethyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and 
         a bond represented by a wavy line indicates a cis form, a trans form, or a mixture of a cis form and a trans form at a desired ratio. 
       
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the low molecular weight compound of the formula (I) is a compound expressed by the following formula (II): 
       
         
           
           
               
               
           
         
         where, in the formulas (II), R 1  represents a hydrogen atom, a halogen atom, a hydroxyl group, or a substituted or unsubstituted C 1-6  alkyl group, 
         R 2  represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group (—NO 2 ), a substituted or unsubstituted C 1-6  alkyloxy group, or a substituted or unsubstituted C 1-6  alkyl group, 
         X represents NH, 
         Z′ represents a 6- or 5-membered monocyclic nitrogen-containing heterocyclic ring, 
         R 4  represents a hydrogen atom, a halogen atom, a hydroxyl group, or a substituted or unsubstituted C 1-4  alkyl group, and 
         a bond represented by a wavy line indicates a cis form, a trans form, or a mixture of a cis form and a trans form at a desired ratio. 
       
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein the compound expressed by the formula (II) is 
       
         
           
           
               
               
           
         
       
     
     
         18 . A method for improving, inhibiting development of, and/or treating neovascular diseases, comprising:
 administering a pharmaceutical composition containing a low molecular weight compound as an active ingredient to a subject, the low molecular weight compound being able to suppress expression of VEGF gene in cells or to reduce production of VEGF protein from cells.   
     
     
         19 . The pharmaceutical composition f according to  claim 15 ,
 wherein the neovascular diseases is retinal and choroidal neovascular diseases, and   wherein the low molecular weight compound of the formula (I) is a compound expressed by the following formula (III):   
       
         
           
           
               
               
           
         
         where, in the formula (III), R 1  represents a hydrogen atom, a halogen atom, a hydroxyl group, or a substituted or unsubstituted C 1-6  alkyl group, 
         R 2  represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group (—NO 2 ), a substituted or unsubstituted C 1-6  alkyloxy group, or a substituted or unsubstituted C 1-6  alkyl group, 
         X represents NH or O, 
         R 5  represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted C 1-4  alkyl group, a substituted or unsubstituted benzyl or heteroarylmethyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, and 
         a bond represented by a wavy line indicates a cis form, a trans form, or a mixture of a cis form and a trans form at a desired ratio. 
       
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the compound expressed by the formula (III) is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and combinations thereof. 
     
     
         21 . The pharmaceutical composition according to  claim 19 , wherein the retinal and choroidal neovascular diseases include age-related macular degeneration, glaucoma, occlusion of the retinal vein, and diabetic retinopathy. 
     
     
         22 . The pharmaceutical composition according to  claim 20 , wherein the retinal and choroidal neovascular diseases include age-related macular degeneration, glaucoma, occlusion of the retinal vein, and diabetic retinopathy.